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Intervention groups | GROUP B | The intervention was one of the following three treatment methods:Group A: Muscular injection of Diphereline 11.25 mg (produced by Ipsen France) in three-month intervals.Group B: Muscular injection of Microrelin 11.25 mg (produced by Homa Pharmed Company) in three-month intervals.Group C: Muscular injection of Microrelin 3.75 mg (produced by Homa Pharmed Company) in monthly intervals. | PMC10638790 | |
Outcomes | The outcomes of the study consisted of serum estradiol and FSH levels and score of menopause symptoms every three months. | PMC10638790 | ||
Blinding description | Blindness, ’ | BLINDNESS | In this study, a trained nurse in the research team recorded demographic and clinical characteristics, outcome results, and randomized allocation to different groups. In the two groups receiving three-month injections, patients and observers (oncologist and nurse) were blinded to the administered drug. Blindness was not possible in the group of monthly drug injection for patients, the nurse and the oncologist. The analyzer was completely blinded to patients’ allocation to the three groups up to the end of the study. | PMC10638790 |
Sample size | During the study, we tried to minimize loss to follow-up by close monitoring of the patients. The primary outcome under investigation was changes in serum estradiol and FSH levels over one year. In a similar study [ | PMC10638790 | ||
Statistical analysis | MRS | Descriptive statistics were used to analyze the demographic and clinical characteristics of all participants in the three treatment groups. The frequency distribution of variables was compared among the groups to ensure proper randomization. The outcome variables were FSH and Estradiol levels and MRS scores which they had been quantitively measured 4 and 5 times during one year, respectively. There was only 8 missing data in three groups, which were excluded from analysis. They did not have normal distributions, so the Friedman test was used to examine changes of MRS scores, FSH and estradiol levels over time and the Kruskal-Wallis test was used to compare the mean difference of outcomes among the groups at each time point of measurement. Moreover, Generalized Estimation Equation (GEE) test was employed to investigate the interaction effect of time variable and treatment groups with the studied repeated measurement outcomes. Significance level of α error equal 5% was considered in the analysis. | PMC10638790 | |
Results | MCI | INTERACTION, IDC, MRS, INVASIVE DUCTAL CARCINOMA | In this study, we performed two interim analyses with 30% and 50% of the anticipated sample size. Both analyses confirmed the non-inferiority of drugs B and C compared to A. So, we achieved a final analysis on 133 patients of group A (n = 43), group B (n = 47), and group C (n = 43). A few participants were excluded as follows: one subject in group A (due to change of the oncologist), four in group B (due to loss to follow-up in MCI clinic), and three in group C (due to loss to follow-up and discontinuation of the drugs) (Fig. Demographic and clinical characteristics of the participants in three arms are shown in Table
Demographic and clinical characteristics of participants and comparison among the groups*Chi-square test** One-Way ANOVA test***Kruskal-Wallis testMRS: Menopause rating scale. Her2: Human epidermal growth factor receptor 2. IDC: Invasive ductal carcinoma. BMI: Body mass index. FSH: Follicle stimulating hormoneTable
Changes in FSH and estradiol during the three-month intervals in groups A, B and CPP
One-year changes in serum FSH Changes in MRS and its subscales scores are summarized in Table
One-year mean changes of MRS score and its subscale within and between groupsPP
One-year changes in the mean score of MRS in the three groups of studyGEE was used to adjust the interaction effect of time and group variables in order to compare the effectiveness and side effects of the drugs among the three groups within the study period of one year (Table Injection of Microrelin 3.75 and Microrelin 11.25 reduced the mean FSH level more than Diphereline 11.25 by up to 0.88 and 1.25 units per three months, respectively.According to the findings (Table
Interaction of time and group effect with the total MRS score, serum estradiol and FSH levels*Adjusted for time and group | PMC10638790 |
Discussion | breast cancers, breast cancer, cancer, cognitive problems, prostate, uterine, and ovarian cancers, depression, vaginal dryness | PREMATURE PUBERTY, STILL, ABNORMAL UTERINE BLEEDING, BREAST CANCER, SIDE EFFECT, CANCER, DRUG SIDE EFFECTS, REGRESSION, DISEASES, COMPLICATIONS | Given the rising trend of breast cancer in the world and in Iran and the ensuing widespread use of GnRH agonists by these patients, physicians and patients must have access to products with the least side effects and the greatest effectiveness. This non-inferiority RCT aimed to compare the effectiveness of two injectable medications, i.e., one-month and three-month Microrelin (Homa Pharmed Company) and three-month Diphereline (IPSEN France), in terms of estrogen and FSH reduction as well as the occurrence of menopause complications and symptoms. Examining the changes in the variables over one year showed that the variations in estradiol and FSH levels as well as the drug side effects and symptoms of menopause did not differ significantly in Microrelin 3.75 and 11.25 mg groups compared to the Diphereline group and they can be considered in Iranian patients’ treatment.During the study period of one year, a decreasing trend was observed in serum FSH and estradiol levels in all three treatment arms. Bellet et al. examined 116 premenopausal patients with breast cancer. After the patients received triptorelin, the estradiol level decreased by more than 95% in months 3, 6, and 12 compared to the outset of the study [Some factors such as the type of chemotherapy regimen, estrogen agonist drugs, and the time of GnRH agonist administration (which can be simultaneously with or after the chemotherapy drug) may affect the performance of the drug and its effectiveness in reducing ovarian function. Still, despite the presence of other factors influencing the effectiveness of cancer treatment, the results of the present study confirmed the effect of all three drugs on FSH and estradiol reduction. Only the level of FSH in the 9th month was slightly lower in the Diphereline group than in the other two groups (P = 0.006), although this finding did not have a marked effect on the overall results of the study, i.e. the comparison of the efficacy and side effects of the three studied drugs over one year. Investigating potential influencing and confounding factors in the effectiveness of GnRH agonists certainly requires independent, extensive, and controlled studies. The effectiveness of the three drugs over time was compared using linear regression and by adjusting the effect of group and time. The results showed that the mean serum estradiol and FSH level reduced by 0.521 and 0.88 units more with Microrelin 3.75 mg injection over three months compared to Diphereline. The injection of Microrelin 11.25 mg also reduced FSH level by 1.25 units more than Diphereline, but it decreased the estradiol level less by 0.66 units. Since the mentioned variations were not significant at the 5% level and showed a very small difference in the one-year efficacy trend curve, the lack of superiority in the efficacy of Diphereline compared to the two Microrelin drugs manufactured in Iran can be confirmed.Therefore, to save foreign exchange costs, reduce the treatment costs of breast cancer, and due to the cost-effectiveness of the two similar drugs manufactured by Homa Pharmed Company, the use of the Iranian GnRH agonist is recommended. Note that GnRH agonists are also administered in the treatment of other diseases such as abnormal uterine bleeding, premature puberty, and prostate, uterine, and ovarian cancers; therefore, the approval of domestic drugs can save costs and develop domestic pharmaceutical industries.The drug efficacy diagram (Fig. The findings of this study showed that during the course of the study, the mean score of total menopausal symptoms increased significantly in all three groups, which demonstrates the effect of all three drugs on the induction of menopause and its symptoms. Still, in none of the three groups was there any specific side effect that led to drug discontinuation, hospitalization, or exclusion from the study –an observation that emphasizes the safety of the two domestically-manufactured drugs. Menopause involves physical symptoms such as hot flashes, psychological symptoms such as depression, cognitive problems, and urinary-reproductive symptoms such as vaginal dryness [This randomized clinical trial was achieved in a breast cancer center in Tehran which their patients were referred from different cities of Iran. It seems that hormonal effect of the studied three GnRH agonists drugs can be generalized to the breast cancers of other centers in this country. Studying the long-term effect of these drugs in future researches can provide valuable evidences for planning the breast cancer treatment protocol in premenopausal women. | PMC10638790 |
Acknowledgements | Breast Cancer | BREAST CANCER | The researchers at the Breast Cancer Research Center appreciate the financial support of Homa Pharmed Company for providing the drug for all studied patients. | PMC10638790 |
Authors’ contributions | Safa Najafi: conceptualization, methodology, investigation, supervision, writing (original draft preparation, review and editing). Maryam Ansari: managing project, data collection, writing (original draft preparation). Zahra Omidi: investigation, data collection, writing (original draft preparation, review and editing). Asiie Olfatbakhsh: conceptualization, writing (original draft preparation). Shiva Moghadam: data curation, writing (original draft preparation); Esmat-o-Sadat Hashemi: conceptualization, writing (original draft preparation). Niki Najafi: data collection, writing (original draft preparation). Shahpar Haghighat: conceptualization, methodology, investigation, formal analyses, investigation, supervision, data curation, writing (original draft preparation, review and editing). All of the authors read and approved the final draft of the manuscript. | PMC10638790 | ||
Funding | A grant from Homa pharmed Company funded the original research. | PMC10638790 | ||
Data Availability | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. | PMC10638790 | ||
Declarations | PMC10638790 | |||
Ethics approval and consent to participate | Breast Cancer | BREAST CANCER | This study was conducted in compliance with the principles of the Declaration of Helsinki. This research was approved by the Ethics Committee of the Breast Cancer Research Center and registered with the code: IR.ACECR.IBCRC.REC.1397.003. All the participants signed written informed consent forms prior to participation in the study. Participants will not be identified in any reports or publications. | PMC10638790 |
Consent for publication | Not Applicable. | PMC10638790 | ||
Competing interests | The authors have no conflicts of interest. | PMC10638790 | ||
Trial availability | This study was registered at the Iranian Registry of Clinical Trials (IRCT) on | PMC10638790 | ||
Abbreviations | Luteinizing hormone-releasing hormone agonistEstrogen receptorprogesterone receptorFollicle stimulating hormoneLuteinizing hormoneGonadotropin releasing hormone | PMC10638790 | ||
References | PMC10638790 | |||
1. Introduction | fatigue, anxiety, gastrointestinal problems, cancer, depression, Cancer | CANCER, PMR, CANCER | Cancer patients receiving chemotherapeutic treatments routinely suffer from distressing physical symptoms such as gastrointestinal problems, fatigue, neurological effects [Recently, non-pharmacological interventions have been commonly suggested to minimize the adverse psychological effects during cancer treatment. Many non-pharmacological interventions were suggested to reduce chemotherapy-related stress, such as cognitive behavioural therapy, problem-solving, yoga [MI is when music, as an agent of change, is used to establish a therapeutic relationship, to help individuals reach goals related to physical, emotional, cognitive, and social needs [Many studies evaluated the effect of MI or PMR as a single intervention, but limited studies evaluated their combined effects on patients’ psychological well-being. Previous studies confirmed that MI combined with PMR had a more significant impact on emotional well-being than MI, and PMR applied alone [Test the feasibility and acceptability of MI combined with PMR in BGC patients receiving chemotherapy.Evaluate the preliminary effects of this combined intervention on anxiety, depression, stress, and QoL among BGC patients receiving chemotherapy.This is the first study testing the effects of MI combined with PMR in the short and long term on psychological outcomes in patients’ home settings, particularly focusing on BGC patients receiving chemotherapy. | PMC10624313 |
2. Methods | PMC10624313 | |||
2.1. Design | MAY | A 2-arm, assessor-blinded pilot randomized controlled trial was conducted at at a chemotherapy unit in an oncology hospital, Hanoi, Vietnam, from March to May 2022. | PMC10624313 | |
2.2. Participants | breast or gynaecological cancer | The inclusion criteria were: (1) women with breast or gynaecological cancer aged 18 years or older; (2) receiving chemotherapy once every three weeks and have at least three chemotherapy cycles left; (3) Have Karnofsky score ≥ 80 [ | PMC10624313 | |
2.3. Study sample | Convenience sampling was used to recruit the participants. The sample size planning followed a rule of thumb for determining an appropriate sample size in which the outcome is a continuous measurement. Julious [ | PMC10624313 | ||
2.4. Randomization and allocation concealment | Blocked randomization procedures with a block size of 8 in 1:1 allocation ratio was performed by an independent researcher who did not involve any steps of the intervention program. A random group allocation list was generated by using the online randomizer ( | PMC10624313 | ||
2.5. The combined intervention PMR and MI procedure | PMR | The participants in the intervention group were required to wear loose-fitting, soft clothes, and entered a private, quiet, dimmed light room to receive a face-to-face training session of PMR combined with MI. The training session was performed by the principal investigator (PI), who is certified in PMR and MI. After being introduced to the program, the effects of MI and PMR on psychological issues, the patients were trained on PMR skills and listening to music. The PI demonstrated step-by-step instructions on PMR, and then the participants performed the return demonstration. The participants were instructed on tensing and relaxing 16 muscle groups in sequence, following face and neck, arms and hands, chest and abdomen, legs and feet (see The control group received standard care, including health assessment, regular health advice and nutrition consultation during chemotherapy by doctors and nurses. To minimize the bias by contacting, weekly phone calls were also carried out to participants to ask about their general health and remind them to return to the hospital in subsequent chemotherapy on time. | PMC10624313 | |
2.6. Outcome measures and instruments | Anxiety, cancer, depression, Depression, Cancer | CANCER, RECRUITMENT, CANCER | The recruitment rate, eligibility, consent rate, refusal rate, reasons for refusal, and attrition rate were recorded to assess the feasibility. Individual face-to-face semi-structured interviews were conducted with ten participants in the intervention group to review the acceptability of the intervention. The interview lasted 20 to 30 minutes which covered four questions:Could you describe your experience after three weeks of practising the intervention?How did you feel after practising?Could you give me some comments or suggestions about the program?Would you want to keep practising the intervention in the future?Participants’ demographic characteristic was collected using a demographic sheet which included age, marital status, education level, employment, family income, stage of cancer, frequency of chemotherapy, and treatment regimen.Anxiety, depression and stress were measured using the short form of the Depression Anxiety Stress Scale (DASS-21) [The Functional Assessment of Cancer Therapy–General (FACT-G) was a 27-item self-report measure used to assess QoL in cancer patients, with Cronbach’s alpha for the scale being 0.89 [ | PMC10624313 |
2.7. Data collection | The baseline data was collected using the demographic sheet, DASS, and FACT-G by an outcome assessor. The outcome assessor was blinded to the study groups to collect data and did not involve any study steps. DASS and FACT-G were re-evaluated after finishing three weeks of self-practice intervention (T1) and three weeks after T1 (T2). The interview to review the acceptability of the intervention was conducted at T1 (see | PMC10624313 | ||
Time points for data collection. | PMC10624313 | |||
2.8. Data analysis | Statistical analyses were performed using SPSS version 25. Appropriate descriptive statistics, such as mean, standard deviation, frequency and percentage, were used to summarize and present the baseline characteristics of the participants and the outcome measures across study time points. The preliminary effects of the intervention on the outcomes were estimated by the bias-corrected Hedges’g effect sizes [Every interview was recorded, followed by exact transcription and managed with Nvivo 12 software. The interview transcriptions were analysed using a qualitative content analysis methodology following Graneheim and Lundman [ | PMC10624313 | ||
2.9. Ethical approval | The pilot study was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from all participants prior to enrollment. The study was approved by The Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee (No. 2021.725), the Ethics Committee in medical research, Nam Dinh University of Nursing, Vietnam, Vietnamese Ministry of Health (No. 2792). | PMC10624313 | ||
3. Result | PMC10624313 | |||
3.1. Feasibility of the study | The whole data collection process was done from 8One participant dropped out (4.2%) at T1 because she changed to another hospital. Three participants dropped out at T2 (12.5%), including two participants in the intervention group due to changing the chemotherapy schedule and feeling exhausted and one in the control group because of the changing chemotherapy schedule (see details in | PMC10624313 | ||
The Consolidated Standards of Reporting Trial (CONSORT) flow diagram. | PMC10624313 | |||
3.2. Preliminary effects of MI combined with PMR on outcome measures | PMC10624313 | |||
3.2.1 Participants’ demographic and clinical characteristics | The mean age of the participants was 52.3 years. Nearly half of the participants (45.8%) obtained a bachelor’s or higher degree. The majority of participants did not have a religious belief (83.3%). More than half of the participants were current workers (58.3%), living in a city area (66.7%), and married (62.5%). The proportion of people with an average income/ person/ month lower than 210 USD accounted for 54.2% ( | PMC10624313 | ||
Baseline demographic information of the participants by group assignment. | cancer, DongBreast cancer | CANCER, MUSCLE RELAXATION | MCP: Music intervention combined with progressive muscle relaxation group, SD: standard deviation VND: Vietnam DongBreast cancer accounted for most of the participants (79.2%). Nearly half of participants were stage 4 cancer (45.8%). The mean time from diagnosis was 20.04 months. Half of the participants were treated with docetaxel, whereas paclitaxel was treated for another 29.2%. Other chemotherapy regimens, such as gemcitabine, vinorelbine, and capecitabine, accounted for 20.8% (see detail in | PMC10624313 |
Baseline clinical characteristics of the participants by group assignment. | MUSCLE RELAXATION | MCP: Music intervention combined with progressive muscle relaxation group, SD: Standard deviation. | PMC10624313 | |
Outcome measures across time between the groups. | Data are presented as mean (standard deviation) at time points.Abbreviations: T0, baseline; T1, 3 weeks from baseline; T2, 6 weeks from baseline, CI: Confidence Interval.# Small sample bias-corrected Hedges’g effect size which corresponds to the standardized mean difference of the mean changes at the underlying time point with respect to T0 between the intervention and control groups. | PMC10624313 | ||
3.3. The acceptability of the intervention | A total of ten participants completed the semi-structured interview, and two themes were generated regarding the acceptability of the intervention. The themes were: (1) Perceived beneficial effect on psychological and physical health and (2) Willing to keep practising in the future. | PMC10624313 | ||
Theme 1: Perceived beneficial effect on psychological and physical health | reduced nausea, vomiting, insomnia, pain | Most participants reported that they had better psychological and physical health after three weeks of self-practice at home. Participants reported feeling comfortable, relaxed, and calm.“Besides, some participants reported positive effects on physical health, such as reduced nausea, vomiting, pain, and insomnia.
| PMC10624313 | |
Theme 2: Willing to keep practising in the future | cancer | CANCER | The participants could feel the positive impacts on their health after the intervention. All the participants were willing to continue practising the intervention in the future and wanted to share the intervention with other cancer patients.
| PMC10624313 |
4. Discussion | depression, breast and gynaecological cancer, anxiety | PMR, RECRUITMENT | This pilot randomized controlled trial provided a novel way that combined MI with PMR to solve psychological issues commonly faced by breast and gynaecological cancer patients receiving chemotherapy. The pilot study results showed a promisingly high feasibility of the combined intervention and a potentially effective strategy for anxiety, depression and stress management in the target population.Our study supported the feasibility of the study with high recruitment and consent rate and acceptable attrition rate (16.7%), which was similar to the previous studies with the attrition rate ranging from 4 to 25% [The current study found that the participants in the intervention group, on average, had greater reduction in anxiety, depression and stress at T1 and T2. The results were consistent with a previous study conducted by Zhou, Li [The mechanism of music intervention on anxiety, depression and stress is based on the idea that music can influence the body and mind in many ways. Music’s rhythm and melody can lower the stress hormone cortisol levels through acting on the hippocampus and peripheral nervous system [PMR is commonly used to manage stress-related issues. When faced with stress, the body produces a series of reactions, including the tense response of muscle groups [The current study found greater improvements in QoL in the intervention group than in the control group at T1 and T2, which was in line with the previous studies [ | PMC10624313 |
Strength and limitation | breast and gynaecological cancer | BLIND | A well-designed pilot randomized controlled trial was adopted in the current study with rigorous randomization allocation and blinded assessor. The intervention was developed basing the evidence and was evaluated by an expert panel. Multiple strategies were used to enhance the adherence rate of the participants at home.However, there are several limitations that need to be acknowledged. Firstly, due to the time limitation and COVID-19 impact, we only conducted the pilot with a small sample size. Larger sample size in further studies is warranted to evaluate the effectiveness of the intervention among women with breast and gynaecological cancer receiving chemotherapy. Secondly, this was conducted in a single centre, which limited the generalizability of our study results. In future studies, it is necessary to conduct in multiple centres. Finally, it is impossible to blind participants or interveners because of the nature of the study [ | PMC10624313 |
Conclusion | depression, breast and gynaecological cancer, anxiety | MUSCLE RELAXATION | Music intervention combined with progressive muscle relaxation was feasible and acceptable to women with breast and gynaecological cancer undergoing chemotherapy. The combined intervention may help manage anxiety, depression and stress in the target population, however, insufficient power pilot study findings should be interpreted with caution. | PMC10624313 |
Supporting information | PMC10624313 | |||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | (DOC)Click here for additional data file. | PMC10624313 | ||
Tensing instruction of 16 muscle groups. | (PDF)Click here for additional data file. | PMC10624313 | ||
Study protocol. | Debra Burns | ONCOLOGY | (DOCX)Click here for additional data file.The authors would like to acknowledge all staff in Chemotherapy Unit H5, International Cooperation & Scientific Research Unit, Hanoi Oncology hospital for their support during data collection. We would like to thank Dr. Thapa Chura Bahadur for his support in language editing. We would like to express our sincere thanks to Prof. Debra Burns, School of Engineering and Technology, US; Prof. John Mondanaro, The Louis Armstrong Department of Music Therapy, US; Prof. Zehra Gok Metin Hacettepe University Faculty of Nursing, Internal Medicine Nursing Department, Turkey, Ms Hoang Thi Thanh Hue, Vietnam-France Psychology Institute, Vietnam for help with content evaluation of the intervention. | PMC10624313 |
Background | BUP-XR (SUBLOCADE | PMC10693082 | ||
Methods | treatment-emergent adverse, OUD | SECONDARY | This was a secondary analysis of a randomized, double-blind, placebo-controlled study in which adults with moderate or severe OUD received monthly injections of BUP-XR (2 × 300-mg doses, then 4 × 100-mg or 300-mg maintenance doses) or placebo for 24 weeks. Abstinence was defined as opioid-negative urine drug screens combined with negative self-reports collected weekly. Each participant’s percentage abstinence was calculated after the first, second, and third maintenance doses in opioid-injecting and non-injecting participants. The proportion of participants achieving opioid abstinence in each group was also calculated weekly. Treatment retention rate following the first maintenance dose was estimated for opioid-injecting participants with Kaplan–Meier method. Risk-adjusted comparisons were made via inverse propensity weighting using propensity scores. Buprenorphine plasma concentration–time profiles were compared between injecting and non-injecting participants. The percentages of participants reporting treatment-emergent adverse events were compared between maintenance dose groups within injecting and non-injecting participants separately. | PMC10693082 |
Results | EVENTS | BUP-XR 100-mg and 300-mg maintenance doses were equally effective in non-injecting participants. However, in opioid-injecting participants, the 300-mg maintenance dose delivered clinically meaningful improvements over the 100-mg maintenance dose for treatment retention and opioid abstinence. Exposure–response analyses confirmed that injecting participants would require higher buprenorphine plasma concentrations compared to non-injecting opioid participants to achieve similar efficacy in terms of opioid abstinence. Importantly, both 100- and 300-mg maintenance doses had comparable safety profiles, including hepatic safety events. | PMC10693082 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12954-023-00906-7. | PMC10693082 | ||
Introduction | OUD, overdose | DISORDER | Opioid use disorder (OUD) and overdose from opioids remain at epidemic levels in the USA despite the availability of effective treatments [Medications for OUD, including buprenorphine, methadone, and naltrexone, have established clinical efficacy and represent the standard of care in clinical practice. However, only approximately 11% of those who need treatment actually receive medications to treat their OUD condition [Buprenorphine extended-release (BUP-XR; RBP-6000; SUBLOCADEOpioid blockade, craving, withdrawal, and abstinence data from BUP-XR Phase 2 and Phase 3 studies in patients with moderate-to-severe OUD showed that buprenorphine plasma concentrations sustained at 2–3 ng/mL (corresponding to ≥ 70% brain | PMC10693082 |
Methods | PMC10693082 | |||
Study design | OI | SECONDARY | This was a secondary analysis of a randomized, double-blind, placebo-controlled study which enrolled treatment-seeking adults who met the Phase 3 study design. After screening, participants entered an open-label run-in phase of up to 2 weeks of treatment with buprenorphine/naloxone sublingual film (induction and stabilization), to achieve daily doses ranging from 8 mg/2 mg to 24 mg/6 mg. After run-in, Eligible participants were then randomly assigned (4:4:1:1) to receive BUP-XR 300 mg/300 mg, BUP-XR 300 mg/100 mg, or volume-matched placeboEach participant’s usual route of opioid use was documented. If more than 1 route was frequently used, then the most severe of those was chosen as the usual route based on the following ranking from least to most severe: oral, nasal, smoking, and injection. Participants whose usual route of opioid use at screening was via injection were classified as opioid-injecting participants (OI), and participants who did not use injection as the usual route of opioid use at screening were classified as non-injecting opioid participants (NIO); herein, we refer to OI and NIO as “populations.”The study was conducted in accordance with principles and requirements of the International Council for Harmonization Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to study-related procedures. The clinical study protocol, informed consent forms, and all other appropriate study-related documents were reviewed and approved by Quorum Review Institutional Review Board. | PMC10693082 |
Analyses | OI | The efficacy and safety analysis set were the same. Both were defined as participants who received at least 1 maintenance dose (third injection on week 9) of 300 mg or 100 mg of BUP-XR. The effects of BUP-XR maintenance dose (300 mg vs. 100 mg) on efficacy and safety outcomes were analyzed separately for OI and NIO. Baseline characteristics were summarized by the maintenance dose groups (BUP-XR 300 mg vs. 100 mg) for OI versus NIO populations. | PMC10693082 | |
Efficacy analyses | OI, psychiatric | DISORDER | Urine drug screens (UDS) and self-reports for opioid use were collected weekly; abstinence at a given week was defined as opioid-negative UDS combined with negative self-reports for opioids (Timeline Followback interviews) [Variables measured before randomization: age, gender, race (black vs. non-black), body mass index, years of opioid use, current alcohol use, current tobacco use, cocaine use (self-reported history or UDS positive at screening), polydrug use (self-reported history or UDS positive at screening), psychiatric disorder, daily opioid use in the past 30 days prior to screening, and last sublingual buprenorphine dose (mg) before the first BUP-XR injection.Variables measured post-randomization and prior to the first maintenance dose on week 9: participant’s percentage cocaine abstinence during weeks 1–9 (combined UDS and self-reports); the most recent results for Clinical Opiate Withdrawal Scale (COWS) [Each participant’s percentage abstinence was calculated after the first (weeks 10–25), second (weeks 14–25), and third (weeks 18–25) maintenance doses as the proportion (%) of negative opioid use results among the corresponding 16, 12, and 8 weekly assessments, respectively. Missing UDS or self-report at a specific visit (or both as a result of study discontinuation) were treated as positive for opioid use for that week (Table Treatment retention, abstinence, and plasma buprenorphine concentrations in opioid-injecting participants. Participants included in the analysis were those who received at least one maintenance dose of BUP-XR (300 mg or 100 mg); this corresponds to randomized participants after excluding: participants from site 020, placebo arm, participants who only had their first and/or second BUP-XR injections, and one participant who missed information on the route of opioid use (i.e., injectable vs. non-injectable). Treatment retention rate following the first maintenance dose was estimated for the OI using the Kaplan–Meier method with risk adjustment via propensity score IPW. Time to treatment discontinuation was defined as the number of days from the first maintenance dose until the last scheduled visit for opioid assessment observed in the study. Participants who completed the study were censored at their last opioid assessment visit. | PMC10693082 |
Pharmacokinetic analyses | BLOOD | Blood samples were collected to measure buprenorphine plasma concentrations at weekly visits, with additional samples collected 4 and 24 h after each BUP-XR injection. Buprenorphine plasma concentration was determined using a validated liquid chromatography and tandem mass spectrometric method with a lower limit of quantification of 0.05 ng/ml [ | PMC10693082 | |
Exposure–response analyses | OI | Exposure–response relationships were evaluated for the OI and NIO populations separately. Buprenorphine plasma concentrations were categorized into bins, and the percentage of observations indicating abstinence (negative UDS and self-report) was calculated for each concentration bin and plotted against buprenorphine levels. Consistent with previous concentration–response analyses [ | PMC10693082 | |
Safety analyses | treatment-emergent adverse, OI, TEAEs | HEPATIC DISORDERS | Safety data were analyzed for both BUP-XR maintenance dose groups (100 mg and 300 mg) within OI and NIO separately using the safety analysis set (participants who received at least one maintenance dose). The percentage of participants (incidence proportion) reporting treatment-emergent adverse events (TEAEs) was summarized by BUP-XR injection (1–6), where the denominator was the number of participants receiving that injection. The percentage of participants (incidence proportion) with TEAEs was also summarized separately for the treatment initiation (the first and second 300-mg injections) and maintenance dosing periods, where the denominator was the number of participants who received at least 1 injection during the corresponding period and was the same for both initiation and maintenance dose periods. During the initiation period, almost all participants had 2 BUP-XR injections of 300 mg (except one opioid-injecting participant in the 300-/100-mg group with one 300-mg injection). Analyses were repeated for serious/severe TEAEs and TEAEs of special interest, including injection site reactions, signs and symptoms associated with opioid withdrawal, and hepatic disorders, and for participants meeting the following liver enzyme criteria: elevated alanine aminotransferase [ALT] > 3 × upper limit of normal [ULN], aspartate aminotransferase [AST] > 3 × ULN, or ALT and AST > 3 × ULN at the same time. | PMC10693082 |
Results | PMC10693082 | |||
Discussion | OI, OUD | SECONDARY | Overall, no significant difference in the percentage of opioid abstinence was observed between the 100-mg and 300-mg maintenance doses in non-injecting opioid participants, suggesting that the two dosing regimens performed equally well in this population. Conversely, in opioid-injecting participants, the 300-mg maintenance dose delivered clinically meaningful improvements compared with the 100-mg maintenance dose, in terms of both opioid abstinence and treatment retention. Furthermore, the safety profiles of 300-mg and 100-mg maintenance doses were comparable in both populations.The differences in injecting participants’ mean percentage of abstinence between the 2 maintenance dose groups (Table The results of secondary analyses align with our previous exposure–response modeling work conducted on opioid abstinence using the same Phase 3 data [Findings also align with earlier literature demonstrating that higher doses of buprenorphine are needed to block the subjective effects of higher doses of a full agonist such as hydromorphone [From a safety perspective, both maintenance doses of BUP-XR were well tolerated, as previously reported [One plausible explanation for the present findings is that, on average, OI are more opioid-tolerant than non-injecting participants, possibly due to changes in Overall, the current findings have implications for harm reduction approaches in the treatment of OUD across 3 key domains: public health, clinical practice, and patient-centeredness [A potential limitation of this study is that we did not compare BUP-XR 300 mg versus 100 mg during the maintenance dose period in the randomized intent-to-treat population. As a result, the treatment comparison might be subject to the bias introduced by participants’ discontinuation prior to receiving the maintenance dose. We attempted to limit such bias by performing the efficacy comparison via risk adjustment including both baseline and post-randomization variables. Despite these efforts, unmeasured confounders may have influenced the accuracy of efficacy comparison results. To overcome this limitation and confirm the benefit of BUP-XR 300-mg maintenance dose observed in the OI, a clinical study is currently ongoing to compare the efficacy, safety, and tolerability of the 100-mg versus 300-mg BUP-XR maintenance doses in participants with high opioid tolerance, including those who inject opioids and/or use high doses of opioids. In this study, treatment-seeking, high-risk opioid participants are randomized immediately prior to the first maintenance dose and receive twice-longer maintenance treatment than in the Phase 3 study used in the present analysis (8 vs. 4 maintenance doses). | PMC10693082 |
Conclusions | OI, difficult-to-treat | The 100-mg maintenance dose is well tolerated and may achieve sufficient efficacy outcomes in most NIO. In OI—a high-risk and difficult-to-treat population—the benefit of BUP-XR 300-mg maintenance dose is clinically relevant and may reduce harm by improving abstinence and treatment retention. | PMC10693082 | |
Acknowledgements | Editorial support was provided by Claire Daniele, PhD, of SciPubSupport, LLC. | PMC10693082 | ||
Author contributions | CML | CML | BRH, CML, and YZ designed the analyses. CML and YZ analyzed the data. KLW participated in the collection of the data. All authors participated in the interpretation of the results, revised the various drafts of the manuscript, and approved the final version. | PMC10693082 |
Funding | Pain | This study was funded by Indivior, Inc. MKG’s effort was supported by the Gertrude Levin Endowed Chair in Addiction and Pain Biology. | PMC10693082 | |
Availability of data and materials | Data are available from the authors upon reasonable request. All requests for raw and analyzed data will be promptly reviewed by the sponsor delegate to verify whether it is subject to any confidentiality obligations. Patient-related data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality. Any data that can be shared will be released via a data use agreement. | PMC10693082 | ||
Declarations | PMC10693082 | |||
Ethics approval and consent to participate | This study was approved by the Quorum Review Institutional Review Board (IRB# 30013). | PMC10693082 | ||
Consent for publication | Not applicable. | PMC10693082 | ||
Competing interests | CML | EVENTS, CML | CML and YZ are employees of Indivior, Inc. BRH is a former employee of Indivior, Inc. and holds stock. MKG has received compensation for medical education events from Indivior, Inc., unrelated to this manuscript. KLW has received compensation for advisory committee work from Indivior, Inc., unrelated to this manuscript. | PMC10693082 |
References | PMC10693082 | |||
Background | cardio-renal | CELLULAR PROLIFERATION, TYPE 2 DIABETES | The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes. | PMC10339517 |
Methods | renal/cardiovascular death, chronic kidney disease, cardio-renal | REGRESSION, EVENTS, TYPE 2 DIABETES, END-STAGE KIDNEY DISEASE | Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes. | PMC10339517 |
Results | Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09–2.13; | PMC10339517 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12933-023-01916-2. | PMC10339517 | ||
Keywords | PMC10339517 | |||
Background | cardio-renal complications, obesity, type 2 diabetes mellitus, cardio-renal | OBESITY, TYPE 2 DIABETES, TYPE 2 DIABETES MELLITUS, COMPLICATIONS | Individuals with type 2 diabetes mellitus are at increased risk of cardio-renal complications. Within the altered hormonal milieu among those with type 2 diabetes are changes in the insulin growth factor axis; recent studies have examined the role of insulin growth factor-1 (IGF-1) in the risk for complications from type 2 diabetes [Abnormal concentrations of IGF-1 are linked with obesity [Further research is needed to determine the significance of IGF-1, IGFBP-3, and the ratio between the two in assessing cardio-renal risk, as previous studies have yielded conflicting results regarding their association with adverse clinical outcomes [ | PMC10339517 |
Methods | PMC10339517 | |||
Study design and patient population | heart failure, death, renal death, HF | HEART FAILURE, END-STAGE KIDNEY DISEASE | The trial design, baseline patient characteristics, and the main study results from the CREDENCE trial have been published previously [In this analysis, only those study participants with available plasma for analysis of IGF-1 and IGFBP-3 at baseline were included (N = 2627). Plasma samples were collected at baseline, 1 year, and 3 years, and stored at – 80 ℃ degrees centigrade. IGF-1 was measured using an automated electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany). This method is standardized against the WHO International Standard 02/254. Detection limit was 7 ng/mL and coefficient of variation for repeatability was ≤ 3.5%There were 4 main goals of this analysis. First, we determined the distribution of biomarkers at baseline. Second, we evaluated canagliflozin’s effect on biomarker concentrations from baseline to 1 year and baseline to 3 years. Third, we evaluated the association between biomarker concentrations at baseline (or their change from baseline to Year 1) and cardiovascular (CV) and kidney outcomes. Clinical endpoints examined included the primary composite endpoint of CREDENCE (a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/CV death), the renal composite endpoint (a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal death), as well as the composite of heart failure (HF) hospitalization or CV death, HF hospitalization, all-cause death, and CV death. Fourth, we evaluated the effect of canagliflozin on risk as a function of concentrations of IGF-1, IGFBP-3, or their ratio. | PMC10339517 |
Statistical analysis | REGRESSION, DIABETES MELLITUS | Biomarkers were log transformed because of their skewed distribution. Median (interquartile) and count (frequency) were used to present continuous and categorical variables. Kruskal–Wallis, ANOVA, and chi-square tests were used to compare the baseline characteristics of study population across IGF-1 quartiles, IGFBP-3, and IGF-1/IGFBP-3 ratio as appropriate. To evaluate the effect of canagliflozin on biomarker concentrations, comparisons of geometric mean (95% CI) concentrations were performed in Years 1 and 3. For change from baseline to Year 1, a base linear model was constructed for each log-transformed biomarker at Year 1 by selecting important baseline covariates in patients randomized to placebo in the main study based on Bayesian Information Criterion. The candidate covariates at baseline included continuous variables: age, eGFR, body mass index, systolic blood pressure, hemoglobin A1c, duration of diabetes mellitus, UACR, log transformed NTproBNP and categorical variables: history of HF, and history of diuretic treatment. Cox proportional hazard regression was implemented to assess the association between biomarker concentrations with clinical outcomes, including treatment and treatment-by-biomarker interaction in the models with selected covariates. To do so, log-transformed concentrations of IGF-1 and IGFBP-3 or their ratio were evaluated with hazard ratio (HR) and 95% CI expressed per 1-unit change in each measure. Additionally, dichotomous cutoffs for IGF-1 based on age were also applied All hypotheses were 2-sided, with a p-value < 0.05 considered statistically significant. All statistical analyses were performed using the R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria. URL: | PMC10339517 | |
Discussion | CKD, kidney disease, cardio-renal disease, DKD, cardio-renal, diabetes | KIDNEY DISEASE, EVENTS, CELLULAR PROLIFERATION, TYPE 2 DIABETES, INSULIN SENSITIVITY, COMPLICATIONS, DIABETES | In this trial of patients with type 2 diabetes and CKD who were randomized to receive canagliflozin or placebo, we showed that baseline IGF-1 levels and IGF-1/IGFBP-3 ratio (but not IGFBP-3 concentrations) were associated with cardio-renal outcomes. Higher IGF-1 levels (for a given age) were associated with a greater risk of developing renal and all-cause mortality events. 3 years of therapy with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations. Lastly, the benefits of canagliflozin to reduce cardio-renal events in this high-risk population were consistent across IGF-1 and IGFBP-3 strata. These findings provide evidence regarding the role of the IGF axis in risk for cardio-renal disease.IGF-1 is an anabolic hormone that regulates cellular proliferation, apoptosis, and several metabolic pathways in the human body. Nearly all 98% of IGF-1 is bound to 1 of 6 IGFBPs in circulation. Owing to its longer half-life, IGFBP-3 is the most abundant member of the IGFBP family and accounts for 80% of all IGFBPs [While enhancing insulin sensitivity, growth-promoting properties of IGF-1 are proposed to play a role in developing complications of diabetes [Despite the proposed mechanistic role of IGF-1 in DKD, results of clinical studies investigating the association between IGF-1 levels and kidney disease are inconclusive. In the NHANES study (National Health and Nutrition Examination Survey), Teppala and colleagues [Findings of our study corroborate studies indicating a detrimental association between elevated IGF-1 (when above age-specific cutoffs) as well as higher IGF-1/IGFBP-3 ratio on kidney function. As IGF-1 levels decrease by age, the findings from this study highlight the importance of considering IGF-1 age-specific cutoffs as well as incorporating the balance of IGF-1 bioactivity (reflected in the IGF-1/IGFBP-3 ratio) when studying IGF biology and cardio-renal risk. On the other hand, IGFBP-3 was not correlated with baseline kidney function and failed to predict any clinical events. IGFBP-3 has several IGF-1–dependent and IGF-1–independent functions [The exact mechanism of the cardio-renal benefit of canagliflozin is still undetermined [This study had several limitations. First, biomarker data were unavailable for all participants; however, those in this post hoc analysis were similar to the main study. Second, more than 70% of study participants were White. A diverse research population can increase generalizability of our findings. Future studies need to implement the National Institutes of Health recommendations to conduct research studies with diverse ethnic backgrounds. Lastly, patients were followed up for 3 years; a longer duration may be required to investigate the association between IGF-1 and incident HF. | PMC10339517 |
Conclusion | DKD, cardio-renal disease, kidney disease, cardio-renal | TYPE 2 DIABETES | In conclusion, this study provides evidence that elevated IGF-1 levels or the ratio of IGF-1/IGFBP-3 is associated with a higher risk of kidney disease progression and all-cause mortality. Three years of therapy with canagliflozin failed to impact IGF-1 or IGFBP-3 levels. Nonetheless, the benefit of canagliflozin to reduce cardio-renal endpoints was preserved across strata of both biomarkers. These results affirm a role of IGF-1 or its activity in the progression of cardio-renal disease among individuals with type 2 diabetes and DKD. | PMC10339517 |
Acknowledgements | Technical editorial assistance was provided by Kayla Smull, of Lumanity Communications Inc. and funded by Janssen Research & Development, LLC. | PMC10339517 | ||
Author contributions | JJ | JJ, RM, JB, MKH contributed to the conception or design of the work. RM and YL contributed to the acquisition, analysis, or interpretation of data for the work. RM and JJ drafted the manuscript. MKH, YY, NS, JB, CAP, MJ and HJLH critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. | PMC10339517 | |
Funding | The CREDENCE trial and this analysis were funded by Janssen Research & Development, LLC. Canagliflozin was developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Dr. Mohebi is supported by Barry Fellowship. Dr. Januzzi is supported by the Hutter Family Professorship. | PMC10339517 | ||
Availability of data and materials | The data underlying this article cannot be shared publicly due to proprietary restrictions. | PMC10339517 | ||
Declarations | PMC10339517 | |||
Ethics approval and consent to participate | Local ethics committees approved all study procedures for the CREDENCE trial and subsequent analyses. Consent was obtained from all study participants. | PMC10339517 | ||
Consent for publication | Not applicable. | PMC10339517 | ||
Competing interests | HANSEN | Drs. Michael Hansen and Yshai Yavin are full-time employees of Janssen Research & Development, LLC. Dr. Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals and a Director at Jana Care; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. The rest of authors have no disclosure. | PMC10339517 | |
References | PMC10339517 | |||
Background | LRTIs, lower respiratory tract infections | LOWER RESPIRATORY TRACT INFECTIONS | Antibiotics are commonly prescribed for children with lower respiratory tract infections (LRTIs), fuelling antibiotic resistance, and there are few prognostic tools available to inform management. | PMC10664149 |
Aim | To externally validate an existing prognostic model (STARWAVe) to identify children at low risk of illness progression, and if model performance was limited to develop a new internally validated prognostic model. | PMC10664149 | ||
Design and setting | Prospective cohort study with a nested trial in a primary care setting. | PMC10664149 | ||
Method | LRTI | Children aged 6 months to 12 years presenting with uncomplicated LRTI were included in the cohort. Children were randomised to receive amoxicillin 50 mg/kg per day for 7 days or placebo, or if not randomised they participated in a parallel observational study to maximise generalisability. Baseline clinical data were used to predict adverse outcome (illness progression requiring hospital assessment). | PMC10664149 | |
Results | A total of 758 children participated ( | PMC10664149 | ||
Conclusion | LRTI | A simple three-item prognostic score could be useful as a tool to identify children with LRTI who are at low risk of an adverse outcome and to guide clinical management. | PMC10664149 | |
INTRODUCTION | fits, LRTI | LOWER RESPIRATORY TRACT INFECTION, LRTI, COMPLICATION | Lower respiratory tract infection (LRTI) is a frequent trigger for attendance in primary care, where nearly all children are managed, most receiving antibiotics.Judicious and targeted use of antibiotics is likely to be key to both efficient clinical care and minimising the risk of antibiotic resistance. Clinicians are risk averse to a child developing a complication when a prescription has not been issuedHow this fits inTrial data alone can be less useful in generating prognostic models because of the inevitable selection bias (where more unwell children tend to be excluded), but nesting trial data within observational studies increases external validity of analyses and facilitates the generation of more robust clinical prediction models. The current study reports data on the progression of illness from a cohort of children that combines trial and observational data. Both the external validation of an existing prognostic model, and since the performance of the existing model was limited in this cohort of more unwell children, the development of a new internally validated model are reported. | PMC10664149 |
METHOD | PMC10664149 |
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